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Effects of oestrogen replacement on steady and pulsatile haemodynamics in ovariectomized rats.

ABSTRACT: 1. The effects of ovariectomy (Ovx), menopause and oestrogen replacement on the haemodynamics remain controversial. The present study employed the technique of arterial impedance analysis to measure and calculate the steady and pulsatile haemodynamics. The purpose was to determine the haemodynamic consequence of ovariectomy and oestrogen replacement. 2. Ovariectomy was carried out under anaesthesia on female Sprague Dawley rats aged 9 weeks. Oestrogen (17 beta-estradiol or E(2)) replacement started 1 week after ovariectomy for 4 weeks. Ovx increased the body weight (BW), while it greatly reduced the uterus weight. Left ventricular weight (LVW) was slightly increased, but LVW/BW ratio was slightly reduced. These changes were reversed after E(2) replacement. 3. Compared to sham group, Ovx with or without E(2) replacement did not significantly affect the systolic, mean and diastolic pressure. In Ovx, pulse pressure (PP) and heart rate were significantly increased, while stroke volume and cardiac output were slightly decreased. Total peripheral resistance (TPR) was largely elevated, indicating Ovx induced systemic vasoconstriction. These changes all returned to close normal values (sham group) after E(2) replacement, except PP. 4. Ovx increased the characteristic input impedance (Zc) and pulse wave reflection, while it decreased arterial compliance. E(2) treatment reversed these changes, except Zc. 5. These results demonstrate that Ovx influences both the resistance and Windkessel functions of the artery. E(2) treatment effectively reverses most the effects of Ovx both on the steady and pulsatile haemodynamics.

SUBMITTER: Lam KK

PROVIDER: S-EPMC1573410 | biostudies-other | 2002 Jul

REPOSITORIES: biostudies-other

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Project description:OBJECTIVE:Progesterone (P4) plays a central role in women's health. Synthetic progestins are used clinically in hormone replacement therapy (HRT), oral contraceptives, and for the treatment of endometriosis and infertility. Unfortunately, synthetic progestins are associated with side effects, including cardiovascular disease and breast cancer. Botanical dietary supplements are widely consumed for the alleviation of a variety of gynecological issues, but very few studies have characterized natural compounds in terms of their ability to bind to and activate progesterone receptors (PR). Kaempferol is a flavonoid that functions as a non-steroidal selective progesterone receptor modulator (SPRM) in vitro. This study investigated the molecular and physiological effects of kaempferol in the ovariectomized rat uteri. METHODS:Since genistein is a phytoestrogen that was previously demonstrated to increase uterine weight and proliferation, the ability of kaempferol to block genistein action in the uterus was investigated. Analyses of proliferation, steroid receptor expression, and induction of well-established PR-regulated targets Areg and Hand2 were completed using histological analysis and qPCR gene induction experiments. In addition, kaempferol in silico binding analysis was completed for PR. The activation of estrogen and androgen receptor signalling was determined in vitro. RESULTS:Molecular docking analysis confirmed that kaempferol adopts poses that are consistent with occupying the ligand-binding pocket of PRA. Kaempferol induced expression of PR regulated transcriptional targets in the ovariectomized rat uteri, including Hand2 and Areg. Consistent with progesterone-l ke activity, kaempferol attenuated genistein-induced uterine luminal epithelial proliferation without increasing uterine weight. Kaempferol signalled without down regulating PR expression in vitro and in vivo and without activating estrogen and androgen receptors. CONCLUSION:Taken together, these data suggest that kaempferol is a unique natural PR modulator that activates PR signaling in vitro and in vivo without triggering PR degradation.

Project description:The effect of oestrogen replacement therapy (ERT) on stroke incidence and severity has been extensively debated. Clinical trials of ERT have demonstrated an increased risk of stroke in treated women, although the study participants were well past menopause when therapy was initiated. It has been suggested that detrimental effects of ERT may be unmasked after prolonged periods of hypoestrogenicity. To date, very few studies have examined the effect of ERT in aged animals, although the timing of replacement may be critical to the neuroprotective effects of ERT. We hypothesised that chronic ERT initiated in late middle age would decrease infarct size in the brain after an induced stroke, whereas acute ERT would have no beneficial effects in aged females. To test this hypothesis, two paradigms of ERT were administered to aged mice of both sexes aiming to determine the effects on stroke outcome and to explore the possible mechanisms by which ERT interacts with age. Female mice that received chronic ERT from 17-20?months of age showed improved stroke outcomes after experimental stroke, whereas females that had acute ERT initiated at 20?months of age did not. Chronic ERT females exhibited diminished levels of nuclear factor kappa B (NF-?B) translocation compared to acute ERT females after stroke. Acute ERT females demonstrated both an increase in nuclear NF-?B and enhanced expression of pro-inflammatory cytokines. In addition, a sexual dimorphic effect of ERT was seen because males benefited from ERT, regardless of the timing of initiation. Aged males had significantly reduced expression of pro-inflammatory markers after stroke compared to age-matched females, suggesting a pro-inflammatory milieu emerges with age in females. These results are consistent with the emerging clinical literature suggesting that ERT should be initiated at the time of menopause to achieve beneficial effects. The present study demonstrates the importance of using appropriate animal models in preclinical studies.

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Effects of oestrogen replacement on steady and pulsatile haemodynamics in ovariectomized rats.

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